All bacteria have developed clever mechanisms for survival and propagation within host cells. Salmonella are a typical example: usually they hide in membrane-bound particles with only very few bacteria escaping to the cell's interior. Those escapees are extremely dangerous as they proliferate and spread at enormous speed. To stop such an invasion, cells have developed very effective defense strategies. An interdisciplinary team around Prof. Ivan Dikic (Institute of Biochemistry II) and Prof. Mike Heilemann (Institute of Physical and Theoretical Chemistry), both from Goethe University Frankfurt, now studied such a cellular defense mechanism by visualizing protein patterns at the near-molecular level.
Upon bacterial invasion, cells react fast: They flag escaped bacteria with a small protein called ubiquitin, which is known to regulate numerous cellular processes. The attached flags contain chains of differently linked ubiquitin molecules, resulting in a secret code, which has so far only partially been decoded. Similar to mobile transmission towers, these ubiquitin chains relay specific signals from the surface of the bacteria into the cell.
Employing super-resolution microscopy, the Frankfurt team now succeeded with visualizing different ubiquitin chains on the bacterial surface and analyzing their molecular organization in detail. They discovered that one chain type, so called linear chains, plays an essential role during a bacterial invasion. Linear ubiquitin chains trigger degradation of bacteria and kick off an inflammatory signaling cascade which results in restricting bacterial proliferation. In addition, the researchers identified the enzyme Otulin as an important regulator capable of limiting this reaction - a very important notion considering the fact that excessive inflammation is one of the major causes of tissue damage following bacterial infection.
Signaling the cells' need for pathogen defense is just one important role of ubiquitin. The small protein is also involved in development and progression of inflammatory and neurodegenerative diseases as well as of cancer. Until now, however, very little is known about how small errors in the ubiquitin system contribute to these serious human diseases, and how the system can be targeted pharmaceutically.
These new findings pave the way for many follow-up projects which may ultimately lead to novel therapeutic approaches. Very recently, Ivan Dikic obtained one of the prestigious ERC Advanced Grants of 2.5 M € in which he will investigate the role of ubiquitin in modulating the host-pathogen interaction in more detail.
The work of the Frankfurt team is an excellent example for interdisciplinary collaboration and was enabled by funding of several large research networks, e.g. the Cluster of Excellence Macromolecular Complexes, the CRC 1177 on selective autophagy and the LOEWE ubiquitin network. The results are now published in the latest online issue of Nature Microbiology, back-to-back with complementary insights generated by colleagues in Cambridge (UK).

Salmonella within a human cell, surrounded by a coat of different ubiquitin chains. Purple represents linear ubiquitin chains, green all ubiquitin chains. Visualized by super-resolution microscopy (dSTORM). Credit: Mike Heilemann/Ivan Dikic With drug resistance being on the rise worldwide, bacterial infections pose one of the greatest global threats to human health. By deciphering the host-pathogen interaction on a molecular level, researchers hope to pave the way for new therapies. Studying the cell's reaction to Salmonella, scientists from Goethe University Frankfurt have now made a critical discovery to this respect.
All bacteria have developed clever mechanisms for survival and propagation within host cells. Salmonella are a typical example: usually they hide in membrane-bound particles with only very few bacteria escaping to the cell's interior. Those escapees are extremely dangerous as they proliferate and spread at enormous speed. To stop such an invasion, cells have developed very effective defense strategies. An interdisciplinary team around Prof. Ivan Dikic (Institute of Biochemistry II) and Prof. Mike Heilemann (Institute of Physical and Theoretical Chemistry), both from Goethe University Frankfurt, now studied such a cellular defense mechanism by visualizing protein patterns at the near-molecular level.
Upon bacterial invasion, cells react fast: They flag escaped bacteria with a small protein called ubiquitin, which is known to regulate numerous cellular processes. The attached flags contain chains of differently linked ubiquitin molecules, resulting in a secret code, which has so far only partially been decoded. Similar to mobile transmission towers, these ubiquitin chains relay specific signals from the surface of the bacteria into the cell.
Employing super-resolution microscopy, the Frankfurt team now succeeded with visualizing different ubiquitin chains on the bacterial surface and analyzing their molecular organization in detail. They discovered that one chain type, so called linear chains, plays an essential role during a bacterial invasion. Linear ubiquitin chains trigger degradation of bacteria and kick off an inflammatory signaling cascade which results in restricting bacterial proliferation. In addition, the researchers identified the enzyme Otulin as an important regulator capable of limiting this reaction – a very important notion considering the fact that excessive inflammation is one of the major causes of tissue damage following bacterial infection.
Signaling the cells' need for pathogen defense is just one important role of ubiquitin. The small protein is also involved in development and progression of inflammatory and neurodegenerative diseases as well as of cancer. Until now, however, very little is known about how small errors in the ubiquitin system contribute to these serious human diseases, and how the system can be targeted pharmaceutically.
These new findings pave the way for many follow-up projects which may ultimately lead to novel therapeutic approaches. Very recently, Ivan Dikic obtained one of the prestigious ERC Advanced Grants of 2.5 M € in which he will investigate the role of ubiquitin in modulating the host-pathogen interaction in more detail.
Explore further: Tracing down linear ubiquitination: New technology enables detailed analysis of target proteins

All bacteria have developed clever mechanisms for survival and propagation within host cells. Salmonella are a typical example: usually they hide in membrane-bound particles with only very few bacteria escaping to the cell's interior. Those escapees are extremely dangerous as they proliferate and spread at enormous speed. To stop such an invasion, cells have developed very effective defense strategies. An interdisciplinary team around Prof. Ivan Dikic (Institute of Biochemistry II) and Prof. Mike Heilemann (Institute of Physical and Theoretical Chemistry), both from Goethe University Frankfurt, now studied such a cellular defense mechanism by visualizing protein patterns at the near-molecular level.
Upon bacterial invasion, cells react fast: They flag escaped bacteria with a small protein called ubiquitin, which is known to regulate numerous cellular processes. The attached flags contain chains of differently linked ubiquitin molecules, resulting in a secret code, which has so far only partially been decoded. Similar to mobile transmission towers, these ubiquitin chains relay specific signals from the surface of the bacteria into the cell.
Employing super-resolution microscopy, the Frankfurt team now succeeded with visualizing different ubiquitin chains on the bacterial surface and analyzing their molecular organization in detail. They discovered that one chain type, so called linear chains, plays an essential role during a bacterial invasion. Linear ubiquitin chains trigger degradation of bacteria and kick off an inflammatory signaling cascade which results in restricting bacterial proliferation. In addition, the researchers identified the enzyme Otulin as an important regulator capable of limiting this reaction - a very important notion considering the fact that excessive inflammation is one of the major causes of tissue damage following bacterial infection.
Signaling the cells' need for pathogen defense is just one important role of ubiquitin. The small protein is also involved in development and progression of inflammatory and neurodegenerative diseases as well as of cancer. Until now, however, very little is known about how small errors in the ubiquitin system contribute to these serious human diseases, and how the system can be targeted pharmaceutically.
These new findings pave the way for many follow-up projects which may ultimately lead to novel therapeutic approaches. Very recently, Ivan Dikic obtained one of the prestigious ERC Advanced Grants of 2.5 M € in which he will investigate the role of ubiquitin in modulating the host-pathogen interaction in more detail.
The work of the Frankfurt team is an excellent example for interdisciplinary collaboration and was enabled by funding of several large research networks, e.g. the Cluster of Excellence Macromolecular Complexes, the CRC 1177 on selective autophagy and the LOEWE ubiquitin network. The results are now published in the latest online issue of Nature Microbiology, back-to-back with complementary insights generated by colleagues in Cambridge (UK).

The attachment of ubiquitin was long considered as giving the „kiss of death", labelling superfluous proteins for disposal within a cell. However, by now it has been well established that ubiquitin fulfils numerous additional duties in cellular signal transduction. A team of scientists under the lead of Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University Frankfurt, has now discovered a novel mechanism of ubiquitination, by which Legionella bacteria can seize control over their host cells. Legionella causes deadly pneumonia in immunocompromised patients.
According to the current understanding, the coordinated action of three enzymes is needed for attaching ubiquitin to other proteins. In April this year, U.S. scientists described an ubiquitination reaction that depends only on a single enzyme from Legionella bacteria. The Dikic team together with the group of Ivan Matic (Max Planck Institute for Biology of Ageing, Cologne, Germany) now elucidated the underlying molecular mechanism of its action and revealed a hitherto unknown type of chemical linkage between ubiquitin and target proteins.
Their discovery breaks new ground in the field. Sagar Bhogaraju, researcher in the Dikic laboratory, comments: "Most exciting is of course the question if this unusual ubiquitination also occurs in human cells independently of bacterial infection and if there are similar, so far unknown enzymes in humans, which may have a profound influence on cellular processes."
When studying the new mechanism in more detail, the Frankfurt scientists were very surprised to find that the Legionella enzyme does not only transfer ubiquitin onto target proteins, but also chemically manipulates the remaining pool of ubiquitin molecules. Modified ubiquitin almost completely inhibits the conventional ubiquitination system, thereby revealing a new role for this enzyme during Legionella infections.
Several important cellular processes are affected by this shut-down of the ubiquitination system, which can also cause a rapid cell death. The Dikic team showed for example that modified ubiquitin prevents degradation of mitochondria (a process called mitophagy), affects transduction of inflammatory signals and constrains protein degradation.
"Most likely, Legionella is not the only bacterium using this mechanism. We hope that our results help to identify new strategies for the development of antibacterial agents, which could complement conventional antibiotics by limiting cellular damage induced by bacterial enzymes", explains Dikic the high medical relevance of their discovery.
The group of Ivan Dikic is located at both the Institute of Biochemistry II and the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt and has previously contributed significantly to a paradigm change in the ubiquitin field. Ivan hypothesized early on that ubiquitin signals are recognized and translated by specialized domains in other proteins. He identified ubiquitin-binding domains in more than 200 ubiquitin receptors and was able to prove their role in diseases like cancer, amyotrophic lateral sclerosis and Parkinson's.

The attachment of ubiquitin was long considered as giving the "kiss of death", labelling superfluous proteins for disposal within a cell. However, by now it has been well established that ubiquitin fulfils numerous additional duties in cellular signal transduction. A team of scientists under the lead of Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University Frankfurt, has now discovered a novel mechanism of ubiquitination, by which Legionella bacteria can seize control over their host cells. Legionella causes deadly pneumonia in immunocompromised patients.
According to the current understanding, the coordinated action of three enzymes is needed for attaching ubiquitin to other proteins. In April this year, U.S. scientists described an ubiquitination reaction that depends only on a single enzyme from Legionella bacteria. The Dikic team together with the group of Ivan Matic (Max Planck Institute for Biology of Ageing, Cologne, Germany) now elucidated the underlying molecular mechanism of its action and revealed a hitherto unknown type of chemical linkage between ubiquitin and target proteins.
Their discovery breaks new ground in the field. Sagar Bhogaraju, researcher in the Dikic laboratory, comments: "Most exciting is of course the question if this unusual ubiquitination also occurs in human cells independently of bacterial infection and if there are similar, so far unknown enzymes in humans, which may have a profound influence on cellular processes."
When studying the new mechanism in more detail, the Frankfurt scientists were very surprised to find that the Legionella enzyme does not only transfer ubiquitin onto target proteins, but also chemically manipulates the remaining pool of ubiquitin molecules. Modified ubiquitin almost completely inhibits the conventional ubiquitination system, thereby revealing a new role for this enzyme during Legionella infections.
Several important cellular processes are affected by this shut-down of the ubiquitination system, which can also cause a rapid cell death. The Dikic team showed for example that modified ubiquitin prevents degradation of mitochondria (a process called mitophagy), affects transduction of inflammatory signals and constrains protein degradation.
"Most likely, Legionella is not the only bacterium using this mechanism. We hope that our results help to identify new strategies for the development of antibacterial agents, which could complement conventional antibiotics by limiting cellular damage induced by bacterial enzymes", explains Dikic the high medical relevance of their discovery.
The group of Ivan Dikic is located at both the Institute of Biochemistry II and the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt and has previously contributed significantly to a paradigm change in the ubiquitin field. Ivan hypothesized early on that ubiquitin signals are recognized and translated by specialized domains in other proteins. He identified ubiquitin-binding domains in more than 200 ubiquitin receptors and was able to prove their role in diseases like cancer, amyotrophic lateral sclerosis and Parkinson's.